The proposed work aims to further elucidate the molecular mechanisms of erythrocyte sickling: to ascertain the nature and location of binding sites between molecules involved in the polymerization of deoxyhemoglobin S, the role of non-S hemoglobins in sickling interactions, and factors which modify or inhibit sickling. Specific studies include the interaction of various alpha and beta chain variants with Hb S within erythrocytes and in solutions, studies of the inhibition of sickling by alkylation of Hb S with nitrogen mustard and other alkylating agents, and investigation of the effect of variations in multiple parameters (pH, ionic environment, pO2, per cent oxy Hb, pCO2) on sickling of red cells from persons with sickle cell anemia and other sickling variants.